Highly Specific Targeting of the TMPRSS2/ERG Fusion Gene in Prostate Cancer Using Liposomal Nanotechnology.

摘要

The TMPRSS2/ERG fusion gene is found in about 55 % of prostate cancer (PCa) patients. It is absolutely specific for PCa cells, since the fusion transcript is only present in these cells. There is heterogeneity in the structure of the 5 end of the mRNA transcripts of the fusion gene. Some prostate cancers express a single mRNA type, while others express multiple isoforms of the fusion gene that arise via alternative splicing of the initial fusion transcript. We seek to target the four most common and biologically active alternatively spliced fusion gene transcript isoforms using SiRNAs to obtain maximal biological activity in cancers expressing a specific isoform or a combination of isoforms. We propose to use of systemically administered nanolipsomal siRNAs specifically targeting the TMPRSS2/ERG mRNA fusion junctions in orthotopic prostate cancer model in mice. Because this fusion gene is highly specific to PCa we do not expect off-target effects in normal tissues or minimal toxicity. Our results support the efficacy of this approach in in vivo PCa models.